Zartler Zing FBDD Jul2014

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  My Talk on the Future of FBDD
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  • 1. Fragonomics The –omics that will have real impact? Edward R. Zartler, Ph.D Quantum Tessera Consulting
  • 2. The Silk Road 2
  • 3. Central Asian Cultures
  • 4. The –omics Revolution •Genomics •Chemogenomics •Metabo*ics •Genochenomics •Proteomics •Toxicogenomics •Transcriptomics •Fragonomics 4
  • 5. Fragonomics • Sample More “Chemical Space” • Better Chance of Finding Starting Point • All MedChem is Deliberate and Efficient • Highly Integrated Process Zartler and Shapiro (2005) Curr. Opin. Chem. Biol., 9:366. 5
  • 6. Fragments are Ubiquitous •(Almost) every Big Pharma has FBHG integrated into their process •Smaller companies are doing it. •Institutes are doing it. •Academics are doing it •Birds are doing it, bees are doing it. 6
  • 7. Fragonomics Comes in Many Flavors •Anabolic –Find the active, build it up –Find the active -> Analog by Catalog/Collection •Catabolic –Fast follower, patent busting •Multiple Binding –Synergy
  • 8. The Empires of the Silk Road, 3rd Century 8 Parthians Persians Xiongnu Kushans Han
  • 9. The Pieces are Interchangeable •Libraries •Screening •Prosecution is the Key 9
  • 10. The Pieces are Interchangeable Libraries •Libraries –Big –Small –Diverse –Biased –2D –3D 10
  • 11. Library Selection •Choice of approach affects choice of library Anabolic Catabolic known inhibitor Biased Diverse Novel Lead N Me Too Y PK Y Betterment N Multiple First Binder Diverse N Biased Y Y N Second Fragment From 2002
  • 12. 2D vs. 3D Fragments •Is this an either/or proposition? –Shouldn’t be…like anything its compromise •The ideal library would be: –Primarily 2D fragments (very planar) “Chemical Space” –Large enough to cover sufficient chemistry space –No need for Built-in SAR (sufficent readily accessible follow up) –Portion of 3D fragments, but related to the 2D members “Vector Space” –Rapidly accessible follow up fragments for SAR 12
  • 13. How to Get More 3D-arity 13 H O H H H H O H H H H H Bicyclo(1.1.1)pentane -> Phenyl isostere Meanwell (2011) J. Med. Chem. 54, 2529. 3D Isosteres
  • 14. The Empires of the Silk Road, 13th Century
  • 15. •Primary Screen –Direct Binding Best –NMR (best for PPI), very information rich •Secondary Screen –At least one orthogonal binding method –Indirect methods are check boxes What information would you make a decision on? 15 The Pieces are Interchangeable Screening
  • 16. Indirect vs. Direct Methods •Indirect Methods (Biochem., TS, ITC, MS, etc.) –False negatives, False Negatives, False Negatives •Direct Methods (NMR/SPR/Native-MS) –NMR: Native solution conditions –SPR: Immobilized Protein/Target –Native-MS: Must Fly 16
  • 17. The Pieces are Interchangeable Screening •SPR –But what do off-rates mean? –What’s a slow off mean? •NMR –Super-duper-Awesome, but resource INTENSIVE –Structural Information in the Absence of Structure –Protein QC as you go •Native Mass Spec –Enthalpy only binding –Protein QC as you go 17 It’s a question of resources and will.
  • 18. •Active -> Hit –Analog by Catalog/Collection –Structure is great, but NOT required –Biophysical characterization –Medchemist not required. •Hit Confirmation –MedChemist required? •Structure –Is it necessary? 18 The Pieces are Interchangeable Prosecution
  • 19. What are the Known Unknowns? Do you understand it well enough to make a decision from it? •Kinetics •Thermodynamics –Enthalpically driven binding… –Entropy leads to chaos? 19
  • 20. The Empires of the Silk Road, 15th Century Ottomans Persians Mongols Kushans Ming Europe
  • 21. The Future is Now? •Design principles have been completely co-opted •It is the age of the Biophysicist •Non-structurally enabled targets? –Intrinsically Disordered Proteins –Membrane proteins •Multi-Protein Complexes •Is anything unligandable? 21
  • 22. The Future is Now? •Time to revisit the Past? –RAMPED-UP NMR –Ligand Immobilized SPR –What else? •Internecine warfare –Sound and fury or real war? •Is there one (as a separate field)? 22
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